1, 2-bis (substituted phenyl)-3-tertiary-amino-1-propanols



United States Patent 3,161,646 1,2-BIS(SUBSTITUTED Pl-MNYD-3-TERHARY-AMINQ-l-PROPANQLS Bill Elpern, Walnut (lrcelr, Califi, assignor toSterling Drug inc, New York, N.Y., a corporation of Delaware No Drawing.Filed Feb. 19, 1959, Ser. No. 794,253 18 Claims. (Cl. zen-294.7)

This invention relates to substituted diphenylethane derivatives, and isparticularly concerned with 1,2-bis (substituted phenyl)-3-tertiary-amino-l-propanols further substituted in the 1-position by ahydrocarbon radical having from four to about ten carbon atoms or by aphenyl radical substituted by lower-alkoxy or loweralkylmercaptoradicals. The invention is also concerned with acid-addition andquaternary ammonium salts of said l-propanols and a process for thepreparation of said l-propanols.

Among the compounds included within the scope of my invention are thosehaving the general formula wherein Ar and Ar represent phenyl radicalssubstituted by from one to three radicals selected from the classconsisting of lower-alkoxy, lower-alkylmercapto and halogen; Rrepresents a radical selected fromthe class consisting of alkyl havingfrom four to about ten carbon atoms, cycloalkyl, cycloalkyl-lower-alkyl,phenyl-loweralkyl, and phenyl substituted by from one to three radicalsselected from the class consisting of lower-alkoxy andloWer-alkylrnercapto; and N B represents a basic, aliphatic-type,tertiary-amino radical.

In the above general Formula I, when the group R represents an alkylradical having from four to about ten carbon atoms it can be straight orbranched, thus including such radicals as butyl, isobutyl,tertiary-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl,nonyl, decyl, and the like.

When R represents a cyloalkyl radical it can be an unsubstitutedcycloalkyl radical, preferably having from four to about eight ringmembers, such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, 01' the like; or a loWer-alkylated cycloalkyl radical suchas 2 methylcyclopentyl, 4-ethylcyclohexyl, or the like. A preferredgroup of cycloalkyl radicals are those having five or six ring members,including cyclopentyl, cyclohexyl and lower-alkylated derivativesthereof.

When R represents a cycloalkyl-lower-alkyl radical it includescycloalkyl radicals of the foregoing type joined to a lower-alkylradical having from one to about four carbon atoms, thus including suchradicals as cyclohexylmethyl, Z-cyclohexyl-ethyl, 3-cyclopentylpropyl,2-(4- rnethylcyclohexyDethyl, 4-cyclohexylbutyl, 3-cycloheXylbutyl, andthe like.

When R represents a phenyl-lower-alkyl radical it includes lower-alkylradicals having from one to about four carbon atoms substituted by aphenyl radical, thus including such radicals as benzyl, Z-phenylethyl,3-phenylpropyl, Z-phenylpropyl, 4-phenylbutyl, and the like.

When lower-alkoxy or lower-alkylmercapto radicals are present assubstituents of Ar and/ or Ar in the above general formula I, theypreferably contain from one to about four carbon atoms, and thus includesuch specific radicals as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, methylmercapto, ethylmercapito, propylmercapto,isopropylmercapto, butylmercapto, isobutylmercapto, and the like. Whenhalogen radicals are present as substituents of Ar and/ or Ar, they canbe any of the of Formula I.

four halogens, fluorine, chlorine, bromine or iodine. The radicals Arand Ar can be the same or different in any given compound.

When R in the above general Formula I represents a phenyl radicalsubstituted by IoWer-aIkOXy or loweralkyl-mercapto radicals, thelower-alkoxy and loweralkylmercapto radicals are of the same type asthose described above in connection with the substituents of Ar and Ar.

In the above general Formula I, N=B represents a basic, aliphatic-type,tertiary-amino radical. These tertiaryamines are of the type -N(Y) (Y')wherein Y and Y are aliphatic substituents such as lower-alkyl,cycloalkyl, alkenyl and the like or where Y and Y are joined to form anon-aromatic type heterocyclic ring. A preferred group of N B includesthe radicals di-lowenalkylamino, 1- piperidyl, l-pyrrolidyl, and4-morpholinyl, and loweralkylated derivatives of said l-piperidyl,l-pyrrolidyl, and 4-morpho-linyl radicals. In the di-lower-alkylaminoradicals the lower-alkyl radicals can have from one to about six carbonatoms and can be the same or difierent.

The compounds of my invention are prepared according to the followingreaction scheme:

(I) (III) The starting materials of Formula II belong to a known classof desoxybenzoin derivatives, and are readily prepared by aFriedel-Crafts reaction between a substituted phenylacetyl chloride,CICOCH Ar', and a substituted benzene, ArI-I. The desoxybenzoin (II) isreacted with formaldehyde and a secondary amine, HN B, either in thefree form or acid-addition salt form, and a 1,2-bis (substitutedphenyl)-3-tertiary-amino-l-propanone (HI) is thus obtained. The reactionis carried out under conditions commonly used for the Mannich reaction,e.g., in the presence of an inert reaction medium at a temperaturebetween about 50 C. and 150 C.

The amino ketone (III) is then reacted with a Grignard reagent, RMgX,wherein X is halogen selected from chlorine, bromine and iodine, and theresulting intermediate complex is hydrolyzed to produce anamino-carbinol. The Grignard reaction is carried out in an inertreaction medium at a temperature between about 0 C. and 150 C. i

The compounds Off the invention are most conveniently used in the formof water-soluble, non-toxic acidaddition and quaternary ammonium salts,which are the full equivalents of the compounds herein particularlyclaimed. Non-toxic salts are therapeutically acceptable salts whoseanions are relatively innocuous to animal organisms in therapeutic dosesof the salts, so that the beneficial physiological properties inherentin the free bases are not vitiated by side-effects ascribable to theanions; in other words, the latter do not substantially increase thetoxicity inherent in the cations. Appropriate acid-addition salts arethose derived from mineral acids such as hydrochloric acid, hydrobrornicacid,hydriodic acid, nitric acid, sulfuric acid, and phosphoric acid;and organic acids such as acetic acid, citric acid, lactic acid,tartaric acid, ethanesulfonic acid, and quinic acid. The quaternaryammonium salts are obtained by the addition of esters of strong acids tothe free base form of the compounds, said esters having a molecularweight less than about 200. A preferred class of esters comprises alkyl,alkenyl, and monocarbocyclic aryl-lower-alkyl esters of strong inorganicacids or organic sulfonic acids, including such compounds as methylchloride, methyl The acid-addition salts are prepared either bydissolving the free base in an aqueous solution containing theappropriate acid, andisolating the salt by evaporating the solution, orby reacting the free base and acid in an organicsolvent, in which casethe salt separates directly or can be obtained by concentration of thesolution.

The quaternary ammonium salts are prepared by mixing the free base andester of a strong acid in an inert solvent. Heating may be used tofacilitate the reaction, although salt formation usually takes placereadily at room temperature. The quaternary ammonium salt separatesdirectly or can be obtained by concentration of the solution.

It is also possible to convert one quaternary ammonium salt to anotherin which the anion is different. If the anion of the original quaternarysalt forms a waterinsoluble silver salt, the quaternary salt will reactwith silver oxide in aqueous medium to form the correspond ingquaternary ammonium hydroxide, the original anion being removed as aprecipitate. The quaternary ammonium hydroxide solution can then beneutralized with any desired acid, weak or strong, to produce a newquaternary ammonium salt in which the anion is different from that ofthe original salt. In this way quaternary ammonium salts in which theanion is derived from a weak acid can be obtained.

Acid-addition and quaternary ammonium salts having toxic anions arelikewise useful when employed as intermediates in the purification ofthe free bases and in conversion to other salts, and as characterizingderivatives of the free bases.

The structures of the compounds of the invention are established by themode of their preparation and by chemical analysis establishing thepercentage composition of carbon, hydrogen and nitrogen. The presence ofa single basic nitrogen atom was confirmed by analysis and by saltformation.

Pharmacological evaluation of the compounds of the invention having theFormula I has shown that they are useful as cardiac antiaccelerators.They possess a mode of action somewhat similar to that of veratramineand thus are useful in treatment of hypertensive states. The compoundsof the invention are, however, much less toxic than veratramine; forexample, the former were found to have an intravenous LD value in miceof about 30 mg./kg., and an oral LD of at least several hundred mg./kg.,whereas the values for veratramine were 3.68 $0.24 mg./kg. and 13:2.1mg./kg., respectively. The compounds of the invention are active at doselevels of about 20-100 micrograms per heart when measured on theisolated rabbit heart. When the group R has less than four carbon atomsthe activity falls off markedly. The compounds can be administeredorally as tablets or capsules compounded with conventional excipients,or parenterally or intravenously as aqueous solutions.

Pharmacological evaluation of the compounds of the invention has alsoshown that they are useful as coronary dilator agents. When measured onthe isolated rabbit heart by the method of Luduena et al., J. Am. Pharm.Assoc, Sci. Ed., 44, 363-6 (1955), they exhibited a coronary dilatoractivity ranging from one to ten times that of papaverine.

Endocrinological evaluation of the compounds of the invention having theFormula I in their free base or acid-addition salt tforms has shown thatthey are useful as pituitary inhibitors while lacking the estrogenic orandrogenic effect which usually accompanies such activity. Optimumactivity for pituitary inhibition appears to occur in those compounds inwhich the group R has l from six to eight carbon atoms. The compoundsare utilized in the form of sterile aqueous solutions for intramuscularinjection in the case of the acid-addition salts. In the case of thefree bases, they are prepared for use in the form of sterile aqueous orsaline suspensions or oil solutions for intramuscular injection.Alternatively, the compounds can be administered orally compounded ascapsules or tablets with conventional excipients.

The quaternary ammonium saltsof the compounds of Formula I have beenfound to possess ganglionic blocking activity and thus can be utilizedin the same way as conventional ganglionic blocking agents such astetraethylammonium bromide and hexamethonium.

The following examples will further illustrate the invention withoutlimiting the same thereto.

Example I (a) 1,2-bis(4-metlz0xyphenyl)-3-dimethyfamino-Z-propanone[111; Ar, Ar are 4-CH OC H N=B is 'Nt ozi A mixture of 76.9 g. (0.3mole) of desoxyanisoiu, 25.6 g. (6.314 mole) of dimethylaminehydrochloride, 18.0 g. of paraformaldehyde and 250 ml. of absoluteethanol was refluxed for forty hours. An additional 2.0 g. ofparatformaldehyde was then added and the mixture refluxed for nine hourslonger. The reaction mixture was cooled, diluted with 2-3 volumes ofether, and the product which separated was collected by filtration andwashed with ether. The 78.3 g. of product thus obtained was dissolved inwater and the solution was made basic with 35% sodium hydroxidesolution. The gummy material which separated slowly crystallized uponstanding, and was separated by decanting the supernatant liquid, giving63 g. of l,2-bis(4-methoxyphenyl)-3-dimethylamino-l-propanone, MP. 4347C. The free basewas dissolved in absolute ethanol, made acid to Congored by the addition of 10% alcoholic hydrogen chloride, and the productwas caused to precipitate by the addition of ether. The product wascollected by filtration, giving 55.0 g. of1,2-bis(4-methoxyphenyl)-3-dimethylamino-l-propanone in the form of itshydrochlo ride salt. The analytic sample was recrystallized from anethanol-ether mixture and had the MP. l66.5167.5 C. (corn).

Analysis.-Calcd. for C H NO HCE: C, 65.23; H, 6.92; Cl, 10.14. Found: C,65.04; H, 6.83; Cl, 10.04.

By replacement of the desoxyanisoin in the preceding preparation by amolar equivalent amount of 4,4-diethoxydesoxybenzoin or p-methoxyphenylp-ethoxybenzyl ketone, there can be obtained, respectively, 1,2-bis-(4-ethoxyphenyl)-3-dimethylamino-1-propanone [III; Ar, Ar are 4-C H OC HN=B is N(CH or 1-(4- methoxyphenyl) 2 (4-ethoxyphenyl) 3dimethylamino-l-propanone [III; Ar is 4-CH OC H Ar is 4-C H OC H N=B isN(CH By replacement of the dimethylamine hydrochloride in the precedingpreparation by a molar equivalent amount of diethylamino hydrochloride,dipropylamine hydrochloride, methylethylamine hydrochloride,dibutylamine hydrochloride, dihexylamine hydrochloride, piperidinehydrochloride, pyrrolidine hydrochloride, morpholine hydrochloride, orZ-methylpiperidine hydrochloride, there canbe obtained, respectively,

1,2 bis(4-methoxyphenyl) 3 diethylamino l propanone [111; Ar, Ar are4-CH OC H N=B is 2 5)2],

1,2 bis(4-methoxyphcnyl) 3 dipropylamino 1 propanone [III; Ar, Ar are4-CH OC H N=B is a 7)z],

1,2 bis (4-methoxyphenyl) 3 methylethylamino 1- propanone [III; Ar, Arare 4-CH GC H N=B is s)( 2 5)L 1,2 bis(4-methoxyphenyl) 3 dibutylamino1- propanone [III; Ar, A1" are 4-CH3OC6HQ, N B is 4 9)2],

1,2 bis(4-methoxyphenyl) 3 dihexylamino 1 propanone [III; Ar, Ar are4-CH OC H N B is s 1a)2],

1,2 bis(4-methoxyphenyl) 3 (l-piperidyl) 1 propanone [111; Ar, Ar are4-CH OC H N B is s lol,

1,2 bis(4-methoxypheriyl) 3 (l-pyrrolidyl) 1 propanone [III; Ar, Ar are4-CH OC H N B is i a],

1,2 bis(4-methoxyphenyl) 3 (4-morpholinyl) 1 propanone [111; Ar, Ar are4-CH OC H N B is NC4H30], Of

1,2 -bis(4-rnethoxyphenyl) 3 (2-methyl-1-piperidyl)- l-propanone [IIIgAr, Ar are 4-CH OC H N B is NC5H9(CH3) An excess of methyl iodide wasadded to 6.3 g. of 1,2-bis-(4-methoxyphenyl)-3-dimethylamino-l-propanone in 30 ml. of benzene,and the mixture was heated on a steam bath for five minutes. Thereaction mixture was kept at room temperature overnight, and thecrystalline material which had separated was collected by filtration andwashed with benzene, giving 7.5 g. of1,2-bis(4-methoxyphenyl)-3-dirnethy1amino-l-propanone in the form of itsmethiodide salt. A sample when recrystallized from a methanol-ethylacetate mixture had the m.p. 1940-1945 C. (corr.).

Analysis.--Calcd. for C H INO C, 52.75; H, 5.76; I, 27.87. Found: C,52.68;,H, 5.73; I, 27.95.

1,2 bis(4-methoxyphenyl) 3 dimethylamino 1 propanone methiodide wasfound to be at least as active as tetraethyl-ammoniurn bromide inblockade of the parasympathetic ganglia when measured by the carotidocclusion test in dogs.

(b) 2,3 bis(4-methoxyphenyl) 1 dimethylamino- 5 -methyl 3 hexmzol [1; Ris CH CH(CH Ar and Ar are 4-CH OC H N B is N(CH ].--Isobutyl bromide(16.4 g., 0.12 mole) was added to a stirred suspension of 2.9 g. (0.12mole) of magnesium turnings in 250 ml. of dry ether, the reaction wasinitiated by gentle heating, and the mixture was refluxed until themagnesium had been consumed (aboutthree hours). To the resultingGrignard reagent, cooled to 10 C., was added a solution of 12.5 g. (0.04mole) of 1,2-bis(4-methoxyphenyl)- 3-dimethylamino-1-propanone (preparedfrom 14.0 g. of the hydrochloride salt by reaction with dilute sodiumhydroxide, extraction with ether and benzene, and drying andconcentrating the organic layers) in 200 m1. of dry toluene. The mixturewas allowed to warm to room temperature and the ether was distilled offon a steam bath. The remaining toluene solution was refluxed forthreehours at 90 C. and then allowed to stand at room temperature forabout fifteen hours. The reaction mixture was poured into ice watercontaining 120 g. of ammonium chloride, and the mixture was warmed andstirred on a steam bath for one-half hour to complete hydrolysis. Theorganic layer was separated and the aqueous layer extracted with ether.The combined organic layers were washed with water and concentrated. Theresidue was dissolved in absolute alcohol and made acid to Congo red byadding 5 ml. of concentrated hydrochloric acid. The solution wasevaporated to dryness in vacuo, and the residue crystallized upon addingdry ether, giving 14.5 g. of2,3-bis(4-rnethoxypheny1)-1-dimethylamino-5-methyl-3-hexanol in the formof its hydrochloride salt, mp. 174-180" C. When recrystallized twicefrom an isopropyl alcohol-ether mixture, a sample was obtained with themp. 184.5-186" C. (corn).

Analysis.Calcd. for C23H33NO3-HC1: Cr, 67.71; H, 8.40; CI, 8.69. Found:C, 67.91; H, 8.23; Cl. 8.82.

2,3 bis(4-methoxyphenyl) 1 dimethylamino 5- methyl-3-hexanolhydrochloride was found to have a cardiac decelerator activity of 48micrograms per heart (approximate effective dose, AED when measured uponthe isolated rabbit heart; It had an intravenous toxicity (ALD in miceof 32.6 rug/kg.

By replacement of the 1,2-bis(4-methoxyphenyl)-3-dimethylamino-1-propanone in the preceding preparation by a molarequivalent amount of 1,2 bis(4-ethoxyphenyl) 3 dimethylamino 1propanone,

1 l-methoxyphenyl) 2 (4-ethoxyphenyl) 3 dimethylareino-l-propanone,

1,2 bis(4--methoxyphenyl) 3 diethylamino 1 propanone,

1,2 bis(4-methoxyphenyl) 3 dipropylamino 1 propanone,

1,2 bis(4-methoxyphenyl) 3 methylethylamino 1 propanone,

1,2 bis(4-methoxyphenyl) 3 dibutylamino 1 propanone, I

1,2 bis(4-methoxyphenyl 3 dihexylamino 1 propanone,

1,2 bis(4-methoxyphenyl) 3 (l-piperidyl) 1 propanone,

1,2 bis(4-methoxyphenyl) 3 (l-pyrrolidyl) 1 propanone,

1,2 bis(4-methoxyphenyl) 3 (4-morpholinyl) 1 propanone, or

1,2 bis(4-methoxyphenyl) 3 (Z-methyl 1 piperidyl -1-propanone,

there can be obtained, respectively,

2,3 bis(4-ethoxyphenyl) 1 dirnethylamino 5 methyl- 3-hexanol [1; R is CHCH(CH Ar and Ar are 4-C2H5OC5H4, is N(CH3)2],

2- (4-ethoxyphenyl -3 -(4-methoxyphenyl)-1-dimethylamino-5-rnethyl-3-hexanol [1; R is CH CH(CH Ar is 4--CH OC HAr is 4-C2II5OC6H4, is

2,3-bis(4-methoxyphenyl) 1-diethylamino-5-methyl- 3-hexanol [1; R is CHCH(CH Ar and Ar 3Y3 4-CH3OC6IE4, is

2,3 bis(4-methoxyphenyl) 1-dipropylamino-5-methyl- 3-hexanol [1; R is CHCH(CH Ar and Ar are 4-CH3OC6H4, is N(C3H7)2],

2,3-bis{4-methoxyphenyl) -1-methylethylamino-5- methyl-B-hexanol [1; Ris CH CH(CH Ar and Ar BIC 4-CEI3OCGH4, lS (C2H5)],

2,3-bis (4-methoxyphenyl)-l-dibutylamino-S-methyl- 3-hexanol [1; R is CHCH(CH Ar and Ar 2,3-bis(4-methoxyphenyl)-1-dihexylamino-5-methyl-3-hexanol [1; R is CH CH(CH Ar and Ar 3TB 4-CH3OC6H4, lS N(C5I{13}2],

2,3-bis(4-methoxyphenyl) -1- 1-piperidly)-5-methyl- 3--l1exanol [1; R isCH CH(CH Ar and Ar 3T64-CF30C5H4, is Na l-I 2,3-bis (4-methoxyphenyl)-1- Lpyrrolidly -5-n1ethyl- 3-hexanol [1; R is CH CH(CH Ar and Ar are4-CH3OC6H4, is NC H 2,3-bis (4-methoxyphenyl -l (4-n1orpholinyl-5-rnethyl- 3-hexanol [1; R is CH CH(CH Ar and Ar are 4-CH OC H N B isNC H O], or

2,3-bis(4-methoxyphenyl)-1-(2-methyl-1-piperidyl)- S-methyl-3-hexanol[1; R is CH CH(CH Ar and AI" are 4-C1'I3OC6H4, is

The free base,2,3-bis(4-methoxyphenyl)-l-dimethylamino-5-methyl-3-hexanol can beprepared by treating an aqueous solution of its hydrochloride salt with'an excess of sodium hydroxide solution, and extracting the resultingbase. The free base can then be reacted with various acids and esters,e.g., hydrofluoric acid, hydrobromic acid, quinic acid, ethanesulfonicacid, methyl iodide, ethyl bromide, or benzyl chloride, to give,respectively, the hydrofluoride, hydrobromide, quinate, ethanesulfonate,methiodide, ethobromide, or benzochloride salts of2,3-bis(4-methoxypheny1)-1-dimethylamino-5- methyl-B-hexanol.

The hydrofiuoride salt of 2,3-bis(4-methoxyphenyl)-1-dimethylamino--methyl-3-hexanol can be converted to the hydrochloridesalt by passing is through an ion exchange resin saturated with chlorideion.

2,3 bis(4 methoxyphenyl) 1 dimethylamino 5- methyl-3-hexanol methiodidewas prepared from the free base and an excess of methyl iodide inbenzene solution, and had the M.P. 226.5-228 C. (corr.) whenrecrystallized from a methanol-petroleum ether (Skellysolve C) mixture.

Analysis.--Calcd. for C H INO C, 56.14; H, 7.07; I, 24.72. Found: C,56.23; H, 6.79; I, 25.01.

2,3 bis(4 methoxyphenyl) 1 dimethylamino 5- methyl-3-hexanol methiodidewas found to be at least twice as active as tetraethylammonium bromidein blockade of the sympathetic ganglia when measured by the carotidocclusion method in dogs.

Example 2 2,3 bis(4 methoxyphenyl) 1 dimethylamino 3- nonanol [I; R is(CH CH Ar and Ar' are 4-CH OC H N=B is N(CH was prepared from 12.5 g. of1,2-bis(4-methoxyphenyl)-3-dimethylamino-1- propane and the Grignardreagent from 2.9 g. of magnesium and 19.8 g. of n-hexyl bromide,according to the manipulative procedure described above in Example 1,part (b). There was thus obtained 14.6 g. of 2,3-bis(4-methoxyphenyl)-1-dimethylamino-3-nonanol in the form of itshydrochloride salt, M.P. ISO-183 C. A sample of the hydrochloride saltwhen recrystallized from an isopropyl alcohol-ether mixture had the M.P.184.5186.5 C. (corr.).

Analysis.-Calcd. for C H NO .HCI: C, 68.86; H, 8.79; Cl, 8.13. Found: C,68.64; H, 8.63; Cl, 8.23.

2,3 bis(4 methoxyphenyl) 1 dimethylamino 3- nonanol hydrochloride wasfound to have a cardiac decelerator activity of 50 micrograms per heart(approximate effective dose, AED when measured upon the isolated rabbitheart. This compound was also found to cause an 80% inhibition oftesticular growth in the immature male rat when administeredsubcutaneously at a dose level of mg./kg./day. No androgenic orestrogenic activity was observed at dose levels as high as 40mg./kg./day. These tests taken all together indicate the usefulness ofthis compound as a pituitary inhibitor.

2,3 bis(4 methoxyphenyl) 1 dimethylamino 3- nonanol hydrochloride wasfound to have a coronary dilator activity 9 times that of papaverinewhen measured on the isolated rabbit heart.

Example 3 2,3 bis(4 melhoxyphenyl) 3 cyclohexyl 1dimethylamino-3-pr0panol [I; R is C H Ar and Ar are 4-CH OC H N=B isN(CH Was prepared from 12.5 g. of1,2-bis(4-methoxypher1yl)-3-dimethylamino-1- propane and the Grignardreagent from 2.9 g. of magnesium and 19.6 g. of cyclohexyl bromide,according to the manipulative procedure given above in Example 1, part(b). There was thus obtained 12 g. of 2,3-bis(4- methoxyphenyl) 3cyclohexyl 1 dimethylamino 3- propanol in the form of its hydrochloridesalt, which had the M.P. 212-213 C. (corr.) when recrystallized from anethanol-ether mixture.

Analysis.Calcd. for C H NO .HCl: C, 69.18; H, 8.36; Cl, 8.17. Found: C,69.63; H, 8.32; Cl, 7.77.

2,3 bis(4 methoxyphenyl) 3 cyclohexyl 1 dimethylamino-3-propanolhydrochloride was found to have a cardiac decelerator activity of 54micrograms per heart (approximate effective dose, AED when measured uponthe isolated rabbit heart.

Example 4 2,3 bis(4 methoxyphenyl) 1 dimethylamino 3- undecanol [I; R is(CH )-;CH Ar and Ar are 4-CH OC H N=B is N(CH3) Was prepared from 6.9 g.(0.022 mole) of 1,2-bis(4-methoxyphenyl)-3-dimethylamino-l-propanone andthe Grignard reagent from 1.6 g. (0.066 mole) of magnesium and 12.7 g.(0.066 mole) of n-octyl bromide, according to the manipulative proceduregiven above in Example 1, part (b). There was thus obtained2,3-bis(4-methoxyphenyl)-1-dimethylamino-3-undecanol in the form of itshydrochloride salt, which had the M.P. 163-167 C. (corr.) whenrecrystallized from an acetone-ether mixture.

A,'zalysis.-Calcd. for C H NO .HCl: C, 69.86; H, 9.12; Cl, 7.64. Found:C, 69.69; H, 9.01; Cl, 7.65.

2,3 bis(4 methoxyphenyl) 1 dimethylamino 3- undecanol hydrochloride wasfound to have a coronary dilator activity 5 times that of papaverinewhen measured on the isolated rabbit heart.

Example 5 (a) 1,2 bis(4 methoxyphenyl) 3 diethylamino- J-propanone [III;Ar and Ar are 4-CH OC H N=B is N(C H was prepared from 76.9 ofdesoxyanisoin, 34.4 g. of diethylamine hydrochloride and 20 g. ofparaformaldehyde according to the manipulative procedure described abovein Example 1, part (11). There was thus obtained 41.3 g. of1,2-bis(4-methoxyphenyl)-3-dirnethylamino-l-propanone in the form of itshydrochloride salt, M.P. 137150 C. After conversion to the free base,reconversion to the hydrochloride salt and recrystallization of thisfrom an ethanol-ether mixture, a sample 0111,2- bis (4 methoxyphenyl) 3diethylamino 1 propanone hydrochloride with the M.P. 14l.5l44 C. (corr.)was obtained.

Analysis.Calcd. for C H NO HCl: C, 66.74; H, 7.47; Cl, 9.38. Found: C,66.95; H, 7.64; Cl, 9.52.

1,2 bis(4 methoxyphenyl) 3 diethylamino 1- propanone in the form of itsmethiodide salt had the M.P. 152153 C. (corr.) when recrystallized froman ethyl acetate-methanol mixture.

Analysis.-Calcd. for C H INO C, 54.66, H, 6.26; I, 26.26. Found: C,54.68; H, 6.10; I, 26.04.

(b) 2,3 bis(4 melhoxyphenyl) 1 diethylamino- 3-tridecan0l [I; R is (CHCH Ar and Ar are 4-CH OC H N=B is N(C H can be prepared from 1,2 bis (4methoxyphenyl) 3 diethylamino 1 propanone and n-decylmagnesium bromideaccording to the manipulative procedure described above in Example 1,part (b).

Example 6 (a) 1,2 bis(4-meth0xyphenyl)-3-(1-piperidyl)-1-pr0- panone[III; Ar and Ar are 4-CH OC H N=B is NC H was prepared from 76.9 g. ofdesoxyanisoin, 38.2 g. of piperidine hydrochloride and 20 g. ofparaformaldehyde according to the manipulative procedure described abovein Example 1, part (a). There was thus obtained 74.0 g. of1,2-bis(4-methoxyphenyl)-3-(1-piperidyl)-1-propanone in the free baseform. This was divided into two portions and one of these was convertedto the hydrochloride, and the other to the methiodide salt form. 1,2bis(4-methoxyphenyl)-3-(1-piperidyl)-1-propanone hydrochloride had theM.P. l78180 -C. (corr.) when recrystallized from an ethanol-ethermixture.

Analysis.-Calcd. for C H NO .HCl: C, 67.77,; H, 7.24; Cl, 9.09. Found:C, 67.90; H, 7.33; CI, 8.85.

1,2 bis(4 methoxyphenyl) 3 (l-piperidyl)-1-propanone methiodide had theM.P. 221.5-222.5 C. (corr.) when recrystallized from an ethylacetate-methanol mixture.

Analysis.Calcd. for C H INO C, 55.76; H, 6.10; I, 25.62. Found: C,56.00; H, 6.39; I, 26.06.

(b) 2,3 bis(4-meth0xyphenyl)-5-methyl-I-(I-piperidyl)-3-hexan0l [I; R isCH CH(CH Ar and Ar are 4- CH OC H N=B is NC H was prepared from 17.7 g.(0.05 mole) of 1,2-bis(4-methoxyphenyl)-3-(1-piperidyl)- l-propanone andthe Grignard reagent from 2.9 g. (0.12 mole) of magnesium and 17 .0 g.(0.12 mole) of isobutyl bromide, according to the manipulative procedurede scribed above in Example 1, part (b). There was thus obtained 8.5 g.of 2,3-bis(4-methoxyphenyl)-5-methyl-1- (1-piperidyl)-3-hexanol in theform of its hydrochloride salt, M.P. 193-194.5 C. (corn) whenrecrystallized from an ethanol-ether mixture.

Analysis.-Calcd. for C H NO HC-l: C, 69.70; H, 8.55; CI, 7.91. Found: C,69.90; H, 8.50; Cl, 7.67.

2,3 bis (4-methoxyphenyl) -5-methyl-1-( 1-piperidyl)-3 hexanolhydrochloride was found to have a cardiac decelerator activity of23'micrograms per heart (approximate effective dose, AED when measuredupon the isolated rabbit heart.

- Example 7 (a) 1,2 bis(4-meth0xyphenyl)-3-(4-morph0linyl)-1- propanone[111; Ar and Ar are 4-CH OC H N B is NC H O] was prepared from 76.9 g.of desoxyanisoin, 38.8 g. of morpholine hydrochloride and 18.0 g. ofparaformaldehyde according to the manipulative procedure described abovein Example 1, part (a). There was thus obtained 75.0 g. of1,2-bis(4-methoxyphenyl)-3-(4-morpholinyl)-1-propanone in the form ofits hydrochloride salt, M.P. 186.5-188.5 C. (corn) when recrystallizedfrom a methanol-ether mixture.

Analysis.Calcd. for C H NO .HCI: C, 64.36; H, 6.69; Cl, 9.05. Found: C,64.29; H, 6.83; Cl, 9.13.

1,2 bis (4 methoxyphenyl)-3-(4-nrorpl1olinyl)-1-propanone in the form ofits methiodide salt had the M.P. 194.5-197 C. (corr.) whenrecrystallized from an ethyl acetate-methanol mixture.

Analysis.Calcd. for C H INO C, 53.12; H, 5.68; I, 25.52. Found: C,53.14; H, 5.42; I, 25.76.

(1)) 1,2 bis(4 methoxyphenyl)-1-cycl0pentyl-3-(4- mrph0linyl)-1-pr0panol[1; R is C 11 Ar and Ar are 4-CH OC H N=B is NC H O] can be preparedfrom 1,2 bis(4-methoxyphenyl)-1-(4-morpholinyl)-1-propanone andcyclopentylmagnesium bromide according to the manipulative proceduredescribed above in Example 1, part ([9).

Example 8 2,3 bis(4-methoxyphenyl) 1-dimethylamino-6-methyl- 3-0ctanol[1; R is CH CH CH(CH )CH CH Ar and Ar are 4-CH OC H N=B is N(CH wasprepared from 15.6 g. of 1,2-bis(4-methoxyphenyl)-3-dimethylamino-1-propanone and the Grignard reagent from 3.6 g. of magnesium and 25 g. of1-bromo-3-methylpentane according to the manipulative proceduredescribed above in Example 1, part (11), except that the Grignardreagent was prepared in tetrahydrofuran instead of ether. The productwas recrystallized from an isopropyl alcohol-ethyl acetate mixture togive 13.2 g. of 2,3-bis(4-methoxyphenyD-1-dimethylamino-6-methyl-3-octanol in the form of its hydrochloride salt,M.P. 181.21 83.6 C. (corr.).

Analysis.Ca.lcd. for C H NO HCl: C, 68.86; H,

8.78; CI, 8.13. Found: C, 68.70; H, 8.80; Cl, 8.12. 2,3 bis(4methoxyphenyl)-1-dimethylanfino-6-methyl-3-octanol hydrochloride wasfound to have a coronary dilator activity 3.8 times that of papaverinewhen measured on the isolated rabbit heart.

Example 9 2,3 bis(4 methoxyphenyl)-1-dimethylamin0-5-cycl0-hexyl-3-pentarzol [1; R is CH CH C H Ar and Ar are 4-CH OC H N=B is N(CHwas preparedfrom 15 .6 g. of 1,2 bis(4-methoxyphenyl)-3-dirnethylarriino-1-propanone and the Grignard reagent from 3.6 g. of magnesium and28.6 g. of 2-cyclohexylethyl bromide according to the manipulativeprocedure described above in Example 1, part (b). The product wasrecrystallized from isopropyl alcohol to give 10.0 g. of2,3-bis(4-methoxy- 'phenyl)-1-dimethylamino-5-cyclohexyl-3-pentano1 inthe 10 form of its hydrochloride salt, M.P. 226.0227.0 C. (dec.)(c0rr.).

Analysis.Calcd. for C H NO HCl: C, 70.18; H, 8.73; CI, 7.67. Found: C,70.01; H, 8.66; CI, 7.58.

2,3 bis(4 methoxyphenyl)-1-dimethy1amino-5-cyclohexyl-3-pentanolhydrochloride was found to have a coronary dilator activity 4.6 timesthat of papaverine when measured on the isolated rabbit heart.

Example 10 2,3 bis(4 methoxyphenyl) 1 dimethylamino-B-tridecanol [1; Ris (CI-1 CH Ar and Ar are 4-CH OC H N=B is N(CH was prepared from 15.6g. of 1,2-bis(4- methoxyphenyl)-3-dimethy1amino-l-propanone and theGrignard reagent from 3.6 g. of magnesium and 33 g. of n-decyl bromideaccording to the manipulative procedure described above in Example 1,part (b), except that the Grignard reagent was prepared intetrahydrofuran instead of ether. The product was recrystallized fromethyl acetate to give 12.2 g. of2,3-bis(4-methoXyphenyl)-1-dimethylamino-3-tridecanol, M.P. 165.0166.8C. (com).

Analysis.-Calcd. for C H NO HCl: C, 70.77; H, 9.42; Cl, 7.21; O, 9.75.Found: C, 71.58; H, 9.32; Cl, 7.50; O, 9.55.

2,3 bis(4 methoxyphenyl) 1 dimethylamino-3-tridecanol hydrochloride wasfound to have a coronary dilator activity 4 times that of papaverinewhen measured on the isolated rabbit heart.

Example 11 2,3-bis(4-meth0xyphenyl)-1 dimethylamino-3-decanol [1; R is(CH CH Ar and Ar are 4-CH OC H N=B is N(CH was prepared from 15.6 g. of1,2-bis(4- methoxyphenyl)-3-dimethylamino-l-propanone and the Grignardreagent from 3.6 g. of magnesium and 27 g. of n-heptyl bromide accordingto the manipulative procedure described above in Example 1, part (b),except that the Grignard reagent was prepared in tetrahydrofuran insteadof ether. The product was recrystallized from ethyl acetate to give 11.7g. of 2,3-bis(4-methoxyphenyl)- 1-dimethylamino-3-decanol in the form ofits hydrochloride salt, M.P. 172.4173.2 C. (corr.).

' Analysis.--Calcd. for C H N0 HCl: C, 69.39; H, 8.96; Cl, 7.88. Found:C, 69.34; H, 9.21; Cl, 7.75.

2,3-bis(4-methoxyphenyl) 1-dimethylamino-3-decanol hydrochloride wasfound to have a coronary dilator activity 3 times that of papaverinewhen measured on the isolated rabbit heart.

Example 12 2,3-bis(4-methoxyphenyl)-1 dimethylamino-zS-phenyl- 3-hexan0l[1; R is (CH C H Ar and Ar are 4-CH OC H N=B is N(CH was prepared from35 g. of 1,2-bis(4-methoxyphenyl)-3-dimethylamino-1-propanone and theGrigard reagent from 7.3 g. of magnesium and 60 g. of 3-phenylpropylbromide according to the manipulative procedure described above inExample 1, part (12), except that the Grignard reagent was prepared intetrahydrofuran instead of ether. The product was recrystallized fromethyl acetate to give 29 g. of 2,3- bis(4-methoxyphenyl)-1-dimethylamino6-phenyl-3-hexanol in the form of its hydrochloride salt, M.P. 187.0-188.2 C. (corn).

Analysis.-Calcd. for C H NO .HCI: C, 71.55; H, 7.72; O, 10.21. Found: C,71.46; H, 7.91; O, 10.10.

Example 13 i 2,3-bis(4-methoxyphenyl)-1 dimethylamz'nol-methyl-3-un'decan0l [1; R is CH(CH3)C7H15, Ar and Ar are 4-CH OC H N=B is N(CHcan be prepared from 1,2-bis(4-methoxyphenyl) -3dimethylarnino-l-propanone and the Grignard reagent from l-methyloctylbromide according to the manipulative procedure described above inExample 1 part (b).

1 1 Example 14 1,I,Z-tris(4-methoxyphenyl) 3 dimethylamino-l-propanel[1; R, Ar and Ar are 4CH OC H N=B is 3)2]- A solution of4-methoxyphenylmagnesium bromide [prepared from 56.1 g. (0.3 mole) of4-bromoanisole and 7.2 g. (0.3 mole) of magnesium in 250 ml. of dryether] was treated at C. with a solution of 31.3 g. (0.1 mole) of1,2-bis(4-methoxyphenyl)-3 dimethylamine 1 propanone in 400 ml. oftoluene. The ether was removed by distillation, and the remainingmixture was refluxed (internal temperature 108 C.) for three hours.After standing at room temperature for about fifteen hours, the mixturewas hydrolyzed by pouring it into 1 liter of ice water containing 275 g.of ammonium chloride. The organic layer was separated, the aqueous layerextracted with three 75 ml. portions of benzene, and the combinedorganic solutions Washed twice with water. The solvent was removed invacuo, the residue triturated with absolute alcohol and filtered. Thealcoholic filtrate was concentrated in vacuo, giving 63.5 g. of1,l,2-tris(4-methoxyphenyl)-3-dimethylamino-l-propanol, in the form of adark red oil. The methiodide of1,1,2-t1is(4-methoxyphenyl)-3-dimethylamino- 1-propanol, prepared byheating a portion of the free base in benzene solution with an excess ofmethyl iodide, had the M.P. l94.6-196.9 C. (corr.) when recrystallizedtwice from an ethyl acetate methanol mixture.

Analysis.Calcd. for C H 1NO C, 57.57; H, 6.08; I, 22.52. Found: C,57.30; H, 6.20; I, 22.08.

The free base, 1,1,2-tris(4-methoxyphenyl)-3-dimethylamino-l-propanol,had the MP. 102.6107.0 C. (corr.).

Analysis.Calcd. for C H NO C, 74.08; H, 7.41; O, 15.18. Found: C, 74.42;H, 7.34; O, 15.30.

By replacement of the1,2-bis(4-methoxyphenyl)-3-dimethylamino-l-propanone in the precedingpreparation by a molar equivalent amount of1,2-bis(4-ethoxyphenyl)-3-dimethylamino-1-propanone,1-(4-methoxyphenyl)-2-(4-ethoxyphenyl) 3 dimethylamino-1-propanone, V1-(4-chlorophenyl)-2-(3 methoxyphenyl) 3 dimethylamino-l-propanone (fromp-chlorophenyl m-methoxybenzyl ketone, dimethylamine andparaformaldehyde), 1,2-bis(4-methylmercaptophenyl) 3dimethylamino-lpropanone (from 4,4-bis(methylmercapto)desoxybenzoin,dimethylamine and paraformaldehyde), 1 ,2-bis (4-methoxyphenyl)-3-diethylamino-1-propanone,1,2-bis(4-methoxyphenyl)-3-dipropylamino-l-propanone, 1,2-bis(4methoxyphenyl)-3-methylethylamino 1 propanone,1,2-bis(4-rnethoxyphenyl)-3-dibutylamino-l-propanone,l,2-bis(4-methoxyphenyl)-3-dihexylamino-l-propanone,1,2-bis(4-methoxyphenyl) -3- l-pyrrolidyl) -1-propanone,l,2-bis(4-methoxyphenyl) 3 (4 morpholinyl)-1-propanone, or1,2-bis(4-methoxyphenyl) 3 (2-methyl-1-piperidyl)-1- propanone,

there can be obtained, respectively,

1,2-bis (4-ethoxyphenyl)-1-(4 methoxyphenyl)-3-dimethylarnino-l-propanol[1; R is 4-CH OC H Ar and Ar are 4-C2H5OCGH4, is

1,2-bis (4-methoxyphenyl -2- (4 ethoxyphenyl)-3-dimethylamino-l-propanol [1; R is 4-CH OC H Ar is 4-CH3OC5H4, A1" is4-C2H5OC6H4, is N(CH3)2],

1-(4-chlorophenyl)-1-(4-methoxyphenyl)-2(3-methoxyphenyl)-3-dimethylamino 1 propanol [1; R is 4- CH OC H Ar is4-ClC 1-1 Ar' is 3-CH OC H N=B is 3)2],

1,2-bis(4-methylrnercaptophenyl)-1 (4meth0xyphenyl)-3-dimethylamino-l-propanol [1; R is 4-CH OC H Ar and Ar are 4-CH SC HN=B is N(CH 1, 1 ,2-tris(4-methoxyphenyl -3-diethylam ino l-propanol R,AI and A1" are 4-CH3OC6H4, lS N(C2H5)2] 12 1,1,2-tris(4-methoxyphenyl)-3-dipropylamino l-propanol [1; R, Ar and Ar are 4-CHOC H N=B is N(C H 1,1,2-tris(4 methoxyphenyl) 3methylethylamino-lpropanol [1; R, Ar and Ar are 4-CH OC H N=B is 3) 25)], 1,1,2-tris(4-methoxyphenyl)-3-dibutylamino l-propanol [1; R, Ar andAr are 4-CH OC H N=B is N(C H 1,1,2-tris(4-methoxyphenyl)-3-dihexylaminol-propanol [1; R, Ar and Ar are 4-CH OC H N=B is e 1a)2],1,1,2-tris(4-methoxyphenyl)-3-(l-pyrrolidyl) l-propanol [1; R, Ar and Arare 4-CH OC H N=B is NC H 1,1,2-tris(4-methoxyphenyl)-3 (4morpholinyl)-1-propanol [1; R, Ar and Ar are CH OC H N=B is NC H O], or1,1,2-tris(4-methoxyphenyl)-3-(2-methyl 1-piperidyl)-1- propanol [1; R,Ar and Ar are 4-CH OC H N=B is NC H (CH Example 151,1,2-tris(4-melh0xyphenyl) 3 I-piperidyl) -1-pr0- panel [1; R, Ar andAr are 4-CH OC H4, N=B is NC H was prepared from 17.8 g. of1,2-bis(4-methoxyphenyl)-3-dimethylarnino-l-propanone, 28.1 g. ofp-bromoanisole and 3.6 g. of magnesium according to the manipulativeprocedure described above in Example 14. The product was recrystallizedfirst from aqueous dimethylformarnide and then from an acetone-ethermixture to give 1,1,2-tris(4-methoxyphenyl)-3 (l-piperdiyD-l-propanol inthe form of its hydrochloride salt, M.P. 120.4- 132.4 C. (corr.).

Analysis.--Calcd. for C29H35N04.HC11 C1, 0,129. Found: C], 6.92; O,12.8.

1,1,2-tris(4-rnethoxyphenyl)-3-(1-piperidyl)-1-propanol hydrochloridewas found to have a coronary dilator activity 1.5 times that ofpapaverine when measured on the isolated rabbit heart. It had anintravenous toxicity (LD in mice of 43i3.6 mg./kg.

Example 16 2-(3,4,5-trimethoxyphenyl) 3 (4-meth0xyphenyl)-1-dimethylamin0-3-n0nan0l [1; R is (CH CH Ar is 4- CH3OC6H4, AI" iS3,4,S-(CH30)3CGH2, is N(CH can be prepared by reacting 4-methoxyphenyl3,4,5-trimethoxybenzyl ketone (prepared by a Friedel Crafts reactionbetween 4-methoxyphenylacetyl chloride and 3,4,5-trimethoxybenzene),dimethylamine and formaldehyde to produce1-(4-methoxyphenyl)-2-(3,4,5-trirrnethoxyphenyl)-3-dimethylamino-l-propanone,and then reacting the latter with n-hexylmagnesium bromide according tothe manipulative procedures described hereinabove.

Example 17 1,2-bis(4-br0m0phenyl)-1-(4 methylmercapt0phenyl)-3-dimethylamino-I-propanol [1; R is 4-CH SC H Ar and Ar are 4-BrC H N=Bis N(CH can be prepared by reacting 4bromophenyl 4-bromobenzyl ketone,di methylamine and formaldehyde to produced 1,2-bis(4-bromophenyl)-3-dimethylarnino-1-propanone, and then reacting the latterwith 4-methylmercaptophenylmagnesium bromide according to themanipulative procedure described hereinabove.

This application is a continuation-in-part of my copending applications,Serial Nos. 638,200, filed February 5, 1957, and now U.S. Patent3,010,965, and 638,430, filed February 6, 1957, and now abandoned.

I claim:

1. Compounds having the formula wherein Ar and Ar'represent phenylsubstituted by from one to three members of the group consisting oflower- 13 alkoxy, lower-alkylmercapto and halogen; R represents a memberof the group consisting of alkyl having from four to ten carbon atoms,cycloalkyl having -6 ring members, cycloalkyl-lower-alkyl having 5-6ring mem bers, phenyl-lower-alkyl, and phenyl substituted by from one tothree members of the group consisting of loweralkoxy andlower-alkylmercapto; and N B represents a member of the group consistingof di-lower-alkyiarnino, l-piperid-yl, l-pyrrolidyl, 4-morpholinyl,lower-alkylated l-piperidyl, lower-alkylated l-pyrrolidyl andlower-alkylated 4-rnorpholinyl.

2. Compounds having the formula R R0 l cn on" on LE2N=B wherein Rrepresents alkyl having from four to ten carbon atoms, R and R"represent lower-alkyl, and N=B represents di-lower-alkylamino.

3. Compounds having the formula sents di-lower-alkylamino.

5. Compounds having the formula wherein R, R and R representlower-alkoxy and N B represents di-lower-alkylamino.

6. Compounds having the formula wherein R, R and R representlower-aikoxy and N=B represents l-piperidyl.

7. 2,3-bis(4-methoxyphenyl) 1 dimethylamino 5 methyl-3-hexanol.

8. 2,3-bis (4 methoxyphenyl) 1 dimethylamino 3 nonanol.

9. 1,2-bis(4-methoxyphenyl) 1 cyclohexyl 3 dimethylamino-l-propanol.

10. 2,3-bis(4 methoxyphenyl 5 methyl 1 (1 piperidyl -3 -hexanol.

11. 2,3-bis(4-methoxyphenyl) 1 dimethylamino 3 undecanol.

12. 2,3-dianisy1 1 dimethylamino 6 methyl 3 octanol.

13. 2,3-bis(4-methoxypheny1) 1 dimethylarnino 5-cyc1ohexy1-3-pentano1.

14. 2,3-bis (4 methoxyphenyl) 1 dimethylamino B-tridecanol.

15. 2,3-bis(4 methoxyphenyl) 1 dimethylarnino 3-decanol.

16. 2,3-bis(4 methoxyphenyl) 1 dimethylamino 6-pheny1-3-hexano1.

17. 1,1,2-tris(4 methoxyphenyl) 3 dimethylamino l-propanol.

18. 1,1,2-tris(4-methoxyphenyl) 3 (l-piperidyl 1 propanol.

References Cited by the Examiner UNITED STATES PATENTS 2,485,662 10/49Rohrman 260294.7 2,515,700 7/50 Denton et a1. 260-294.7 2,599,497 6/52Stoll et a1. 260294.7 2,654,745 10/53 Rhodehamel 260-2947 2,665,278 1/54Schultz 260294.7 2,680,115 6/54 Ruddy et a1. 260-294.7 2,827,460 3/58Stein et a1. 260294.7

FOREIGN PATENTS 265,665 4/50 Switzerland.

269,078 10/ 50 Switzerland.

269,084 10/50 Switzerland.

525,839 5/ 31 Germany.

624,117 5 49 Great Britain.

624,118 5/49 Great Britain.

627,139 7/49 Great Britain.

OTHER REFERENCES Denton et al.: lournal of the American Chemical Society, vol. 71: page 2052 (1949).

Huebner: Journal of Organic Chemistry, vol. 18: pages 736-739 (1953).

IRVING MARCUS, Primary Examiner.

H. I. LIDOFF, D. T. McCUTCI-IEN, Examiners.

. UNITED STATES PATENT OFFICE .CERTIFICATE OF CORRECTION Patent No.3,l6l,6 l6 December 15, 1964 Bill Elpern It is hereby certifiedthat'error appears in the above numbered patent requiring correction andthat the said Letters Patent should read as corrected below.

H H Column 6, line 62 for NC H O read NC H O column 7, lines 26 and 58,for "propane", each occurrence, read propanone column 8, lines 26 and27, for "3dimethylamino" read -3diethylaminocolumn 12, line 9, for "4-CHOC H read l-CI-I OC FI same column 12, lines 70 to 73, the formulashould appear as shown below instead of as in the patent:

Signed and sealed this 11th day of May 1965.

(SEAL) Attest:

ERNEST W. SWIDER Attesting Officer EPWARD J. BRENNER Commissioner ofPatents 1

1. COMPOUNDS HAVING THE FORMULA